The present invention is directed to a novel process for the convenient preparation of .beta.-lactams which can be used for the preparation .beta.-lactams which serve as precursors of the paclitaxel side-chain.
Paclitaxel (Taxol.TM.), isolated in minute quantities from the bark of the pacific yew Taxus brevifolia, is a potent anticancer agent used clinically to treat advanced ovarian and breast cancers. Paclitaxel is a member of the taxane natural products having the following structure: ##STR1##
The difficulties in meeting the growing demand for large quantities of paclitaxel has been circumvented by its semi-synthesis from 10-deacetylbaccatin-III, a taxane isolated from the needles of the English yew Taxus baccata. The structure of 10-deacetylbaccatin-III is shown below: ##STR2##
Semi-synthetic paclitaxel is made from derivatives of 10-deacetylbaccatin-III by coupling a suitable side chain precursor to the free hydroxyl group at position 13. In addition all the total syntheses reported to date the side-chain has been installed in a similar way as one of the late steps..sup.1 The current interest in paclitaxel has therefore created a need for good synthetic routes to such precursors of the C-13 side chain. The side-chain is also a very important structural feature that is, in part, responsible for paclitaxel's impressive ability to stabilise microtubules. As a consequence, many analogues of paclitaxel possessing a modified C-13 side chain have been made by semi-synthesis.
Of the numerous synthetic routes to the side-chain, .beta.-lactams constitute one of the most important type of side-chain precursor and can be made via the Staudinger reaction between an imine and a ketone..sup.2 The .beta.-lactam 3 has previously been made by the Staudinger reaction between the imine 1 and the ketene derived in situ from acetoxyacetyl chloride 2 (3:4, 75:25, 74%)..sup.3 However, the .beta.-lactam was ring-opened in the next step of what constituted a synthesis of the phenylisoserine side-chain: the auxiliary was removed by hydrogenolysis. ##STR3##
Farina and co-workers have also used a similar chiral auxiliary based approach to the synthesis of the C-13 side chain..sup.4 They used a derivative of L-threonine as the auxiliary, as shown below. Although the diastereoselectivity of .beta.-lactam formation is good (10:1), four reactions are required to remove the auxiliary via treatment with fluoride ion, methanesulfonyl chloride and triethylamine, ozone, and sodium bicarbonate in 66% overall yield. These steps necessarily increase the costs of a process and severely limit the number of possible compatible functional groups present in any side chain analogue. Additionally, the L-threonine derivative is not commercially available and would be expensive to make. ##STR4##
A new auxiliary to control the diastereoselectivity in the ringforming reaction which could be made inexpensively and also be removed without destruction of the .beta.-lactam ring in a single step is therefore needed. This could be obtained by the use of p-methoxyphenyl substituted amines. We have now developed a new stereocontrolled route to the paclitaxel .beta.-lactam side-chain precursor using a chiral auxiliary that is cleaved oxidatively from the lactam nitrogen atom.